OP0193 SEX DIMORPHISM ANALYSIS IN A COHORT OF JIA PATIENTS REVEALS DIFFERING GENETIC RISK FACTORS FOR FEMALES AND MALES
Authors: M. Tordoff, S. Smith, A. Morris, S. Eyre, W. Thomson, J. Bowes
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Juvenile idiopathic arthritis (JIA) encompasses a group of childhood onset rheumatic diseases that primarily affect females. JIA has been reported to occur in females and males with a 2:1 ratio, however, systemic JIA is reported to occur equally in sexes and enthesitis-related arthritis (ERA) is reported more frequently in male patients. Genetic risk factors may contribute to the sex dimorphism in JIA incidence, however this contribution has yet to be defined. <h3>Objectives</h3> To investigate, using sex dimorphism analysis, whether genetic risk factors for JIA differ in males and females. <h3>Methods</h3> High quality genotype data was available on 3356 JIA cases (females = 2209, males =1147) and 9196 controls (female =4059, males =5137). Our primary analysis combined sex-specific GWAS summary statistics using the GWAMA software package. Summary statistics were calculated using logistic regression with three principal components as covariates using PLINK. The sex-differentiated p-value (p<sub>diff</sub>) provided overall evidence for association to JIA allowing for differences between males and females,and the heterogeneity p-value (p<sub>het</sub>) provided evidence to support a difference in effect estimates between sexes. As a secondary analysis we performed a logistic regression, as above, on all samples and included sex as an interaction term (p<sub>int</sub>). Amino acid residues in HLA genes and alleles were imputed using SNP2HLA and an association test with sex as an interaction term was implemented on markers of interest. <h3>Results</h3> A total of 6571296 SNPs were analysed after quality control. The strongest signal detected using a logistic regression in females was rs9469137 (<i>p</i> = 1.7x10<sup>-80</sup>) and in males it was rs116666910 (<i>p</i> = 9.7x10<sup>-59</sup>). GWAMA supported evidence of sex heterogeneity for these SNPs, rs9469137 <i>p</i><sub><i>het</i></sub> = 2.2x10<sup>-6</sup>, OR<sub>males</sub> = 2.6, OR<sub>females</sub> = 5.3, rs116666910 <i>p</i><sub><i>het</i></sub> = 1.8x10<sup>-14</sup><sub>,</sub> OR<sub>male</sub> = 4.0, OR<sub>female</sub> = 1.6. The strongest signal from the sex-specific GWAS was rs9266716, <i>p</i><sub><i>het</i></sub> = 1.9x10<sup>-17</sup>, <i>p</i><sub><i>int</i></sub> = 7.7x10<sup>-18</sup>, OR<sub>male</sub> = 1.2, OR<sub>female</sub> = 0.6. These SNPs all map to the HLA region, providing strong evidence for sex dimorphism in this region, therefore sex-specific HLA fine mapping was conducted. This analysis revealed that residues at position 13 of <i>HLA-DRB1</i> were strongly associated with JIA in females (<i>p</i><sub><i>female</i></sub> = 1.8x10<sup>-124</sup>). Glycine at position 13 of <i>HLA-DRB1</i> was most strongly associated with JIA in females (OR<sub>female</sub> = 3.6, <i>p</i><sub><i>female</i></sub> = 4.1x10<sup>-65</sup>, OR<sub>male</sub> =1.9, <i>p</i><sub>male</sub> = 9.6x10<sup>-13</sup>). An association test with sex as an interaction term revealed glycine at position 13 as sex dimorphic, <i>p</i> = 4.3x10<sup>-7</sup>. Associations of residues at position 13 of <i>HLA-DRB1</i> have previously been reported in JIA, where the cohort consisted of oligoarthritis and rheumatoid factor negative polyarthritis individuals. These ILAR subtypes have a greater frequency in females. <i>HLA-B27</i> was detected as strongly associated with JIA in male patients (<i>p</i><sub><i>male</i></sub> =5.4 x10<sup>-64</sup>, OR<sub>male</sub> = 3.8, <i>p</i><sub><i>female</i></sub> = 2.5x10<sup>-9</sup>, OR<sub>female</sub> = 1.6). An association test with sex as an interaction term revealed <i>HLA-B27</i> to be strongly sex dimorphic, <i>p</i> = 7.5x10<sup>-15</sup>. <i>HLA-B27</i> is a well-established risk factor for ERA, where males are predominately affected. Outside of the HLA region, the strongest associated SNP was rs58020114, <i>p</i><sub><i>het</i></sub> = 6.3x10<sup>-7</sup>, <i>p</i><sub><i>int</i></sub> = 5.7x10<sup>-7</sup><sub>,</sub> OR<sub>male</sub> = 1.3, OR<sub>female</sub> =0.7. This SNP is located near the <i>BPNT2</i> gene and had a greater effect size in males. <h3>Conclusion</h3> This analysis reveals that there are several sexually dimorphic genetic risk factors that may affect JIA development in males and females. For the first time markers within the <i>HLA</i> region have been detected as sex dimorphic. Understanding the genetic risk factors to JIA development will help to further define the disease, which may aid in disease classification and diagnosis in the future. In particular, the substantial differences in effect estimates observed between males and females suggests that sex-specific polygenic risk scores should be considered when HLA signals are incorporated into these efforts. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.